Atherosclerosis, a form of arteriosclerosis, is characterized by accumulation of lipids in the aorta and in the coronary, cerebral and peripheral arteries of the lower extremities. As these masses increase in size, the risk of thrombosis and occlusion arises.
It has been found that those suffering from the disease exhibit elevated levels of plasma lipoprotein, of which cholesterol and triglycerides comprise major constituents. While the etiology of the disease is not yet fully understood, it is believed that .beta.-lipoproteins play an important role, and it has been recommended that dietary habits which promote low .beta.-lipoprotein plasma levels be observed. In addition, various therapeutic agents such as estrogens, thyroxine analogs and sitosterol preparations have been used to lower plasma cholesterol levels in individuals prone to the condition.
It has now been found that certain mono- and disubstituted-5-sulfamylbenzoic acids are effective in reducing plasma lipid levels. These compounds can be expected to be useful in the treatment of atherosclerosis and related cardiovascular diseases associated with elevated lipid levels.
A number of 5-sulfamylbenzoic acids are found in the literature:
______________________________________ ##STR1## A B Reference ______________________________________ NH.sub.2 Cl (1) CH.sub.3 NH Cl (2) (CH.sub.3).sub.2 N Cl (2) C.sub.2 H.sub.5 NH Cl (2) (CH.sub.3) (C.sub.2 H.sub.5)N Cl (2) (C.sub.2 H.sub.5).sub.2 N Cl (2) i-C.sub.3 H.sub.7 NH Cl (2) (CH.sub.3) (i-C.sub.3 H.sub.7)N Cl (2) NH.sub.2 Br (3) (CH.sub.3)NH Br (3) (CH.sub.3).sub.2 N Br (3) (C.sub.2 H.sub.5).sub.2 N Br (3) ##STR2## Br (3) (CH.sub.3)NH NH.sub.2 (2) (C.sub.2 H.sub.5)NH NH.sub.2 (2) (C.sub.2 H.sub.5).sub.2 N NH.sub.2 (2) (CH.sub.3) (C.sub.2 H.sub.5)N NH.sub.2 (2) (i-C.sub.3 H.sub.7)NH NH.sub.2 (2) (CH) (i-C.sub.3 H.sub.7)N NH.sub.2 (2) ##STR3## NH.sub.2 (4) (CH.sub.3).sub.2 N C.sub.2 H.sub.5 NH (2) (CH.sub.3).sub.2 N (i-C.sub.3 H.sub.7)NH (2) (CH.sub.3).sub.2 N C.sub.4 H.sub.9 NH (2) ______________________________________ (1) Jackman, et al., J. Pharm. Pharmacol., page 679 (1962) (2) Belgian Patent 620,741 (1963), (Chem. Abstr., 59, 11359) (3) Kunzle, et al., Helvetica Chimica Acta, 52, 625 (1969) (4) U.S. Pat. 2,453,104 (1948), (Chem. Abstr., 43, 7710)
In addition, 4-sulfamylbenzoic acids are found in the literature:
______________________________________ ##STR4## A Reference ______________________________________ (C.sub.3 H.sub.7).sub.2 N (5) (i-C.sub.3 H.sub.7).sub.2 N (5) (C.sub.4 H.sub.9).sub.2 N (5) C.sub.6 H.sub.5 CH.sub.2 NH (5) ##STR5## (5) ______________________________________ (5) British Patent 795,937 (1958) (Chem. Abstr., 53, 297)
A series of sulfamylbenzoic acids with utility as uricosuric agents for rheumatism and arthritis are claimed in West German patent application DT No. 2,109,339. None of the 5-sulfamyl compounds of the present invention, however, demonstrated uricosuric activity when tested.
Although the foregoing summary has been disclosed by a diligent search of the literature, it does not, of course, purport to be an exhaustive listing of all known sulfamylbenzoic acids. Nevertheless, so far as can be determined, the ability of the 5-sulfamylbenzoic acids of the present invention to reduce plasma lipid levels has never before been recognized.